The excitability of sensory neurons depends on the expression of various voltage-gated Na+ channel isoforms. The tetrodotoxin-resistant (TTXr) Na+ channel Na(v)1.8 accounts for the electroresponsiveness of nociceptive neurons and contributes to inflammatory and neuropathic pain. Na+ channel blockers are clinically employed for chronic pain management, but side effects limit their use. There is conflicting information whether their potency to block tetrodotoxin-sensitive (TTXs) and TTXr Na+ channels differs. We analyzed the action of lidocaine and amitriptyline on TTXr Na(v)1.8 heterologously expressed in ND7/23 cells in comparison with TTXs Na+ channels endogenously expressed in ND7/23 cells. TTXr Na(v)1.8 and TTXs currents were investigated under whole-cell voltage-clamp. At a holding potential of -80 mV, lidocaine was 5-fold and amitriptyline 8-fold more potent to tonically block TTXs than Na(v)1.8 currents. This was due to a higher percentage of TTXs channels residing in the inactivated, high-affinity state at this potential. Tonic block of either resting or inactivated channels by lidocaine or amitriptyline revealed little differences between TTXs and Na(v)1.8 channels. Use-dependent block by amitriptyline was similar in TTXs and Na(v)1.8 channels. Surprisingly, use-dependent block by lidocaine was more pronounced in Na(v)1.8 than in TTXs channels. This result was confirmed in dorsal root ganglion neurons and is associated with the greater tendency of Na(v)1.8 to enter a slow inactivated state. Our data suggest that lidocaine could selectively block Na(v)1.8-mediated action potential firing. It is conceivable that the expression pattern of Na+ channels in sensory neurons might influence the efficiency of Na+ channel blockers used for chronic pain management.